The tumor microenvironment creates powerful obstacles for cancer immunotherapy by limiting the expansion of local tumor-specific T lymphocytes, preventing T-cell penetration and the killing of tumor-specific targets. Therefore, therapeutic targeting of the tumor microenvironment combined with immunotherapy is a logical and attractive approach. We have shown that both chemotherapy and treatment targeted to mutated BRAF increased the susceptibility of melanoma cells to the cytotoxic effect of T cells through a dramatic perforin-independent increase in permeability to granzyme B (GrzB) released by activated cytotoxic T cells (CTL). Our data strongly suggested that this effect was mediated via up-regulation of the expression of mannose-6-phosphate receptors (MPR) on the surface of tumor cells while undergoing autophagy. When combined with chemo- or targeted therapy, CTLs raised against specific antigens were able to induce apoptosis in neighboring tumor cells that did not express those antigens, creating a bystander effect. Our preliminary experiments demonstrated that BRAF inhibitors with potent anti-tumor activity against melanoma induced up-regulation of MPR in BFAF mutated melanoma cells, suggesting that they might provide a potent bystander effect with adoptive cell therapy. In the current proposal we will further explore the mechanisms by which targeted and chemotherapeutic agents alter tumor susceptibility to T cell destruction, and propose two clinical trials. In the first trial we will biopsy accessible tumors from patients receiving either a targeted BRAF agent or a chemotherapeutic drug before and after treatment and determine if MPR, markers of autophagy and GrzB are increased on melanoma cells, and when after initiation of treatment increases in these markers can be measured. These findings will then be translated to a phase II trial of the BRAF inhibitor vemurafenib combined with adoptive cell therapy with tumor infiltrating lymphocytes (TIL) and IL-2 after lymphdepletion. This trial will test whether targeted therapy combined with TIL will increase the clinical efficacy of the immunotherapy and result in a higher proportion of patients who do not drop out before they receive their TIL.